Methods for controlling formation of imiquimod impurities for two months, four months, and six months

ABSTRACT

Pharmaceutical formulations and methods including an immune response modifier (IRM) compound and an oleic acid component are provided where stability is improved by using oleic acid have low polar impurities such as peroxides.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/334,255, filed Dec. 12, 2008, now U.S. Pat. No. 7,655,672, whichapplication is a continuation of U.S. application Ser. No. 11/276,324,filed Feb. 24, 2006, which application is a continuation of U.S.application Ser. No. 11/303,659, filed Dec. 16, 2005, now abandonedwhich application claims the benefit of U.S. Provisional ApplicationSer. No. 60/636,916 filed Dec. 17, 2004, the teachings of all beingincorporated herein by reference in their entirety. This applicationalso is a divisional of co-pending U.S. application Ser. No. 11/276,324,filed Feb. 24, 2006, which application is a continuation of U.S.application Ser. No. 11/303,659, filed Dec. 16, 2005, now abandonedwhich application claims the benefit of U.S. Provisional ApplicationSer. No. 60/636,916 filed Dec. 17, 2004, the teachings of all beingincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations for thetopical or transdermal delivery of immunomodifying drugs.

BACKGROUND

There has been a major effort in recent years, with significant success,to discover new drug compounds that act by stimulating certain keyaspects of the immune system, as well as by suppressing certain otheraspects. These compounds, referred to herein as immune responsemodifiers (IRMs), appear to act through immune system mechanisms knownas toll-like receptors to induce selected cytokine biosynthesis. Theymay be useful for treating a wide variety of diseases and conditions.For example, certain IRMs may be useful for treating viral diseases(e.g., human papilloma virus, hepatitis, herpes), neoplasias (e.g.,basal cell carcinoma, squamous cell carcinoma, actinic keratosis,melanoma), and TH2-mediated diseases (e.g., asthma, allergic rhinitis,atopic dermatitis), and are also useful as vaccine adjuvants.

Many of the IRM compounds are small organic molecule imidazoquinolineamine derivatives (see, e.g., U.S. Pat. No. 4,689,338), but a number ofother compound classes are known as well (see, e.g., U.S. Pat. Nos.5,446,153, 6,194,425, and 6,110,929) and more are still beingdiscovered.

One of these IRM compounds, known as imiquimod, has been commercializedin a topical formulation, ALDARA, for the treatment of actinickeratosis, basal cell carcinoma, or anogenital warts associated withhuman papillomavirus.

Pharmaceutical formulations containing IRM compounds are disclosed inU.S. Pat. Nos. 5,238,944; 5,939,090; and 6,425,776; European Patent 0394 026; and U.S. Patent Publication 2003/0199538.

Although some of the beneficial effects of IRMs are known, the abilityto provide therapeutic benefit via topical application of an IRMcompound for treatment of a particular condition at a particularlocation may be hindered by a variety of factors. These factors include:irritation of the skin to which the formulation is applied; formulationwash away; insolubility of the IRM compound in the formulation; chemicaldegradation of the IRM compound and/or other ingredients, physicalinstability of the formulation (e.g., separation of components,thickening, precipitation/agglomerization of active ingredient, and thelike); poor permeation; and undesired systemic delivery of topical IRMformulations if not intended to be transdermal.

Accordingly, there is a continuing need for new and/or improved IRMformulations.

SUMMARY

It has now been found that, while oleic acid can be used to solubilizeIRMs, even difficult to formulate, highly insoluble IRMs, formulationscomprising an IRM compound in combination with oleic acid can sufferfrom impaired stability. Somewhat surprisingly, addition of greateramounts of antioxidants to the formulation does not solve the problem.However, it has been found that utilizing an oleic acid component havingreduced amounts of polar impurities, such as peroxides, aldehydes,alcohols, and ketones in a formulation containing an IRM can reduce theformation of impurities and thereby provide improved formulationstability. Instability is an important issue for pharmaceuticalformulations and can reduce the shelf life of a product or jeopardizeregulatory approvability.

It has been discovered that the stability of a formulation containing anIRM compound and oleic acid can be improved by utilizing an oleic acidcomponent that is free of or contains low amounts of polar impurities,such as peroxides, aldehydes, alcohols, and ketones. Although notintending to be bound to any particular theory or mechanism, it ishypothesized that the higher amounts of polar impurities present in theoleic acid component can react with the IRM compound, therebydestabilizing the formulation and increasing the rate of formation ofimpurities derived from the IRM compound.

In one aspect, the present invention provides a pharmaceuticalformulation comprising a therapeutically effective amount of an immuneresponse modifier (IRM) compound and a pharmaceutically acceptablevehicle including an oleic acid component, wherein the formulation issubstantially free of polar impurities introduced by the oleic acidcomponent.

In another aspect, the present invention provides a pharmaceuticalformulation comprising: a therapeutically effective amount of an IRMcompound and a pharmaceutically acceptable vehicle including an oleicacid component, wherein the oleic acid component has a peroxide value nogreater than 5.

In another aspect, the present invention provides a pharmaceuticalformulation comprising: a therapeutically effective amount of an IRMcompound and a pharmaceutically acceptable vehicle including an oleicacid component, wherein the oleic acid component is at least 80% oleicacid.

The present invention also provides methods.

In one aspect, the present invention provides a method of stabilizing apharmaceutical formulation comprising a therapeutically effective amountof an immune response modifier (IRM) compound and oleic acid by using anoleic acid component that is substantially free of polar impurities.

In one aspect, the present invention provides a method of stabilizing apharmaceutical formulation comprising a therapeutically effective amountof an IRM compound and oleic acid by using an oleic acid component witha peroxide value no greater than 5.

In one aspect, the present invention provides a method of stabilizing apharmaceutical formulation comprising a therapeutically effective amountof an IRM compound and oleic acid by using an oleic acid component thatis at least 80% oleic acid.

In another aspect, the present invention provides methods for treatingdisease, including but not limited to the group comprising actinickeratosis, basal cell carcinoma, genital warts, peri-anal warts,malignant melanoma, and molloscum contagiosum. In another aspect, thepresent invention provides methods to induce cytokine biosynthesis. Inanother aspect, the present invention provides methods to induceinterferon biosynthesis.

A number of additional embodiments can be described as follows:

1. A pharmaceutical formulation comprising:

a therapeutically effective amount of an immune response modifier (IRM)compound selected from the group consisting of imidazoquinoline amines,tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines,imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridineamines, thiazolopyridine amines, oxazolonaphthyridine amines,thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridineamines, quinoline amines, tetrahydroquinoline amines, naphthyridineamines, or tetrahydronaphthyridine amines, and combinations thereof; and

a pharmaceutically acceptable vehicle including an oleic acid component,wherein the formulation is substantially free of polar impuritiesintroduced by the oleic acid component.

2. A pharmaceutical formulation comprising:

a therapeutically effective amount of an IRM compound selected from thegroup consisting of imidazoquinoline amines, tetrahydroimidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridineamines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridineamines, oxazolonaphthyridine amines, thiazolonaphthyridine amines,1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines, and combinations thereof; and

a pharmaceutically acceptable vehicle including an oleic acid component,wherein the oleic acid component has a peroxide value no greater than 5.

3. A pharmaceutical formulation comprising:

a therapeutically effective amount of an IRM compound selected from thegroup consisting of imidazoquinoline amines, tetrahydroimidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridineamines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridineamines, oxazolonaphthyridine amines, thiazolonaphthyridine amines,1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines, and combinations thereof; and

a pharmaceutically acceptable vehicle including an oleic acid component,wherein the oleic acid component is at least 80% oleic acid.

4. A formulation as in any one of the preceding embodiments wherein theIRM compound is selected from the group consisting of amide substitutedimidazoquinoline amines, sulfonamide substituted imidazoquinolineamines, urea substituted imidazoquinoline amines, aryl ether substitutedimidazoquinoline amines, heterocyclic ether substituted imidazoquinolineamines, amido ether substituted imidazoquinoline amines, sulfonamidoether substituted imidazoquinoline amines, urea substitutedimidazoquinoline ethers, thioether substituted imidazoquinoline amines,6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy or arylalkyleneoxysubstituted imidazoquinoline amines, imidazoquinoline diamines, amidesubstituted tetrahydroimidazoquinoline amines, sulfonamide substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline amines, aryl ether substitutedtetrahydroimidazoquinoline amines, heterocyclic ether substitutedtetrahydroimidazoquinoline amines, amido ether substitutedtetrahydroimidazoquinoline amines, sulfonamido ether substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline ethers, thioether substitutedtetrahydroimidazoquinoline amines, tetrahydroimidazoquinoline diamines,amide substituted imidazopyridine amines, sulfonamide substitutedimidazopyridine amines, urea substituted imidazopyridine amines, arylether substituted imidazopyridine amines, heterocyclic ether substitutedimidazopyridine amines, amido ether substituted imidazopyridine amines,sulfonamido ether substituted imidazopyridine amines, urea substitutedimidazopyridine ethers, thioether substituted imidazopyridine amines,and combinations thereof.5. A formulation as in any one of embodiments 1 through 3 wherein theIRM compound is an imidazonaphthyridine amine.6. A formulation as in any one of embodiments 1 through 3 and 5 whereinthe IRM compound is2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.7. A formulation as in any one of embodiments 1 through 3 wherein theIRM compound is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.8. A formulation as in any one of the preceding embodiments wherein theIRM compound is present in an amount of at least 3% by weight, based onthe total weight of the formulation.9. A formulation as in any one of the preceding embodiments wherein theIRM compound is present in an amount of at least 5% by weight, based onthe total weight of the formulation.10. A formulation as in any one of the preceding embodiments wherein theoleic acid component is present in an amount of at least 15% by weightbased on the total weight of the formulation.11. A formulation as in any one of the preceding embodiments wherein theoleic acid component is present in an amount of at least 20% by weightbased on the total weight of the formulation.12. A formulation as in any one of the preceding embodiments wherein theoleic acid component is present in an amount of at least 25% by weightbased on the total weight of the formulation.13. A formulation as in any one of the preceding embodiments wherein theoleic acid component has been purified by chromatography prior to use inthe formulation.14. A formulation as in any one of the preceding embodiments wherein theoleic acid component is plant-derived.15. A formulation as in any one of the preceding embodiments wherein theformulation includes at least one fatty acid other than oleic acid orisostearic acid.16. A formulation as in any one of the preceding embodiments wherein theformulation includes less than 3% isostearic acid by weight based on thetotal weight of the formulation.17. A formulation as in any one of the preceding embodiments wherein theformulation further comprises an antioxidant.18. A formulation as in any one of the preceding embodiments furthercomprising an antioxidant, wherein the antioxidant is butylated hydroxyltoluene or butylated hydroxyanisole.19. A formulation of any one of the preceding embodiments furthercomprising water.20. A formulation of any one of the preceding embodiments furthercomprising a preservative system.21. A formulation of any one of the preceding embodiments furthercomprising an emulsifier.22. A method of stabilizing a pharmaceutical formulation comprising atherapeutically effective amount of an immune response modifier (IRM)compound selected from the group consisting of imidazoquinoline amines,tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines,imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridineamines, thiazolopyridine amines, oxazolonaphthyridine amines,thiazolonaphthyridine amines, 1H-imidazo dimers fused to pyridineamines, quinoline amines, tetrahydroquinoline amines, naphthyridineamines, or tetrahydronaphthyridine amines, and combinations thereof; andoleic acid by using an oleic acid component that is substantially freeof polar impurities.23. A method of stabilizing a pharmaceutical formulation comprising atherapeutically effective amount of an IRM compound selected from thegroup consisting of imidazoquinoline amines, tetrahydroimidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridineamines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridineamines, oxazolonaphthyridine amines, thiazolonaphthyridine amines,1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines, and combinations thereof; and oleic acidby using an oleic acid component with a peroxide value no greater than5.24. A method of stabilizing a pharmaceutical formulation comprising atherapeutically effective amount of an IRM compound selected from thegroup consisting of imidazoquinoline amines, tetrahydroimidazoquinolineamines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridineamines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridineamines, tetrahydroimidazonaphthyridine amines, oxazoloquinoline amines,thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridineamines, oxazolonaphthyridine amines, thiazolonaphthyridine amines,1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines, and combinations thereof; and oleic acidby using an oleic acid component that is at least 80% oleic acid.25. The method as in any one of embodiments 22 through 24 wherein theIRM compound is selected from the group consisting of: amide substitutedimidazoquinoline amines, sulfonamide substituted imidazoquinolineamines, urea substituted imidazoquinoline amines, aryl ether substitutedimidazoquinoline amines, heterocyclic ether substituted imidazoquinolineamines, amido ether substituted imidazoquinoline amines, sulfonamidoether substituted imidazoquinoline amines, urea substitutedimidazoquinoline ethers, thioether substituted imidazoquinoline amines,6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy, or arylalkyleneoxysubstituted imidazoquinoline amines, imidazoquinoline diamines, amidesubstituted tetrahydroimidazoquinoline amines, sulfonamide substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline amines, aryl ether substitutedtetrahydroimidazoquinoline amines, heterocyclic ether substitutedtetrahydroimidazoquinoline amines, amido ether substitutedtetrahydroimidazoquinoline amines, sulfonamido ether substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline ethers, thioether substitutedtetrahydroimidazoquinoline amines, tetrahydroimidazoquinoline diamines,amide substituted imidazopyridine amines, sulfonamide substitutedimidazopyridine amines, urea substituted imidazopyridine amines, arylether substituted imidazopyridine amines, heterocyclic ether substitutedimidazopyridine amines, amido ether substituted imidazopyridine amines,sulfonamido ether substituted imidazopyridine amines, urea substitutedimidazopyridine ethers, thioether substituted imidazopyridine amines,and combinations thereof.26. The method as in any one of embodiments 22 through 24 wherein theIRM compound is an imidazonaphthyridine amine.27. The method as in any one of embodiments 22 through 24 and 26 whereinthe IRM compound is2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.28. The method as in any one of embodiments 22 through 24 wherein theIRM compound is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.29. A method of treating actinic keratosis, the method comprisingapplying a formulation of any one of embodiments 1 through 21 to theskin of a subject.30. A method of treating basal cell carcinoma, the method comprisingapplying a formulation of any one of embodiments 1 through 21 to theskin of a subject.31. A method of treating genital warts, the method comprising applying aformulation of any one of embodiments 1 through 21 to the skin ormucosal surface of a subject.32. A method of treating peri-anal warts, the method comprising applyinga formulation of any one of embodiments 1 through 21 to the skin ormucosal surface of a subject.33. A method of treating molloscum contagiosum, the method comprisingapplying a formulation of any one of embodiments 1 through 21 to theskin of a subject.34. A method of inducing cytokine biosynthesis, the method comprisingapplying a formulation of any one of embodiments 1 through 21 to theskin or mucosal surface of a subject.35. A method of inducing interferon biosynthesis, the method comprisingapplying a formulation of any one of embodiments 1 through 21 to theskin or mucosal surface of a subject.36. A method of treating malignant melanoma, the method comprisingapplying a formulation of any one of the preceding embodiments 1 through21 to the skin of a subject.

The term “substantially free” is used to indicate that the amountpresent in the composition or formulation is below the level that causesdegradation of the active pharmaceutical agent, such that theformulation is unsuitable for pharmaceutical usage, after storage for 4months at 40° C. at 75% relative humidity. The term can also be used todescribe a composition containing less than 10%, less than 5%, less than1%, or less than 0.1% by weight of a given substance.

The term “polar impurities” includes, but is not limited to peroxides,aldehydes, ketones, alcohols, metal ions, and/or substances that causedegradation of the active pharmaceutical agent.

The term “oleic acid component” is used to describe a preformulationsource or composition of matter containing oleic acid, and may includeother fatty acids in addition to oleic acid, including but not limitedto: myristic acid, palmitic acid, palmitoleic acid, margaric acid,isostearic acid, stearic acid, linoleic acid, linolenic acid, and otherfatty acids, or combinations thereof.

The peroxide value is the number that expresses in milliequivalents ofactive oxygen the quantity of peroxide contained in 1000 g of thesubstance as determined by the methods described in the 5th edition ofthe European Pharmacopoeia, Section 2.5.5.

Unless otherwise indicated, all numbers expressing quantities, ratios,and numerical properties of ingredients, reaction conditions, and soforth used in the specification and claims are to be understood as beingmodified in all instances by the term “about”.

All parts, percentages, ratios, etc. herein are by weight unlessindicated otherwise.

As used herein, “a” or “an” or “the” are used interchangeably with “atleast one” to mean “one or more” of the listed element.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION

The present invention provides pharmaceutical formulations that includea therapeutically effective amount of an immune response modifier (IRM)compound selected from the group consisting of imidazoquinoline amines,tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fusedcycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines,imidazonaphthyridine amines, tetrahydroimidazonaphthyridine amines,oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridineamines, thiazolopyridine amines, oxazolonaphthyridine amines,thiazolonaphthyridine amines, and 1H-imidazo dimers fused to pyridineamines, quinoline amines, tetrahydroquinoline amines, naphthyridineamines, or tetrahydronaphthyridine amines, and oleic acid, wherein theoleic acid component contains a low amount of polar impurities,especially peroxides. Surprisingly, the stability of such formulationsis substantially greater than that of similar formulations containing anIRM compound and oleic acid containing conventional oleic acid withhigher amounts of polar impurities such as peroxides, even when theoleic acid component is of compendial grade. Furthermore, theinstability problem of these formulations is not eliminated byadditional antioxidants.

Through utilization of an oleic acid component containing a very lowamount of polar impurities, the subsequent formation of impurities inIRM formulations is significantly reduced as compared to other IRMformulations comprising compendial grades of oleic acid after both theinitial measurement (i.e., its measurement when initially formulated)and under accelerated conditions (when stored for at least 4 months at40° C. and 75% relative humidity), resulting in an increased formulationshelf life.

For certain embodiments, the formulation comprises an IRM compound and apharmaceutically acceptable vehicle including an oleic acid component,wherein the formulation is substantially free of polar impuritiesintroduced by the oleic acid component. For certain embodiments, theformulation comprises an IRM compound and a pharmaceutically acceptablevehicle including an oleic acid component, wherein the oleic acidcomponent has a peroxide value no greater than 5. For certainembodiments, the formulation comprises an IRM compound and apharmaceutically acceptable vehicle including an oleic acid component,wherein the oleic acid component is at least 80% oleic acid.

In certain embodiments, formulations described herein can be in the formof an oil-in-water emulsion such as a cream or a lotion. The oilcomponent of the formulation includes an IRM compound and one or morefatty acids, including oleic acid in an amount sufficient to solubilizethe IRM compound. Optionally, a cream or lotion of the invention cancontain emollients, antioxidants, emulsifiers, viscosity enhancingagents, and/or preservatives. Such components, as well as all others ofthe formulations described herein, are preferably pharmaceuticallyacceptable.

Immune Response Modifying Compounds

Formulations of the invention include an IRM compound. Such compoundsinclude, for example, imidazoquinoline amines including, but not limitedto, substituted imidazoquinoline amines such as, for example, amidesubstituted imidazoquinoline amines, sulfonamide substitutedimidazoquinoline amines, urea substituted imidazoquinoline amines, arylether substituted imidazoquinoline amines, heterocyclic ethersubstituted imidazoquinoline amines, amido ether substitutedimidazoquinoline amines, sulfonamido ether substituted imidazoquinolineamines, urea substituted imidazoquinoline ethers, thioether substitutedimidazoquinoline amines, 6-, 7-, 8-, or 9-aryl, heteroaryl, aryloxy orarylalkyleneoxy substituted imidazoquinoline amines, andimidazoquinoline diamines; tetrahydroimidazoquinoline amines including,but not limited to, amide substituted tetrahydroimidazoquinoline amines,sulfonamide substituted tetrahydroimidazoquinoline amines, ureasubstituted tetrahydroimidazoquinoline amines, aryl ether substitutedtetrahydroimidazoquinoline amines, heterocyclic ether substitutedtetrahydroimidazoquinoline amines, amido ether substitutedtetrahydroimidazoquinoline amines, sulfonamido ether substitutedtetrahydroimidazoquinoline amines, urea substitutedtetrahydroimidazoquinoline ethers, thioether substitutedtetrahydroimidazoquinoline amines, and tetrahydroquinoline diamines;imidazopyridine amines including, but not limited to, amide substitutedimidazopyridine amines, sulfonamide substituted imidazopyridine amines,urea substituted imidazopyridine amines, aryl ether substitutedimidazopyridine amines, heterocyclic ether substituted imidazopyridineamines, amido ether substituted imidazopyridine amines, sulfonamidoether substituted imidazopyridine amines, urea substitutedimidazopyridine ethers, and thioether substituted imidazopyridineamines; 1,2-bridged imidazoquinoline amines; 6,7-fusedcycloalkylimidazopyridine amines; imidazonaphthyridine amines;tetrahydroimidazonaphthyridine amines; oxazoloquinoline amines;thiazoloquinoline amines; oxazolopyridine amines; thiazolopyridineamines; oxazolonaphthyridine amines; thiazolonaphthyridine amines; and1H-imidazo dimers fused to pyridine amines, quinoline amines,tetrahydroquinoline amines, naphthyridine amines, ortetrahydronaphthyridine amines.

These immune response modifier compounds are disclosed in, e.g., U.S.Pat. Nos. 4,689,338; 4,929,624; 5,266,575; 5,268,376; 5,346,905;5,352,784; 5,389,640; 5,446,153; 5,482,936; 5,756,747; 6,110,929;6,194,425; 6,331,539; 6,376,669; 6,451,810; 6,525,064; 6,541,485;6,545,016; 6,545,017; 6,573,273; 6,656,938; 6,660,735; 6,660,747;6,664,260; 6,664,264; 6,664,265; 6,667,312; 6,670,372; 6,677,347;6,677,348; 6,677,349; 6,683,088; 6,756,382; U.S. Patent Publication Nos.2004/0091491; 2004/0132766; 2004/0147543; and 2004/0176367; andInternational Patent Application No. PCT/US04/28021 filed on Aug. 27,2004.

For certain of these embodiments, the IRM compound is animidazonaphthyridine amine. For certain of these embodiments, the IRMcompound is2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine.For certain of these embodiments, the IRM compound is animidazoquinoline amine. For certain of these embodiments, the IRMcompound is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine(imiquimod). For some embodiments, the IRM may have low solubility inwater, for example less than about 1 ug/mL (e.g., 0.79 ug/mL in the caseof imiquimod), making them difficult to solubilize in aqueousformulations, and potentially using relatively large amounts of oleicacid in the formulation.

The amount of IRM compound that will be therapeutically effective in aspecific situation will depend on such things as the activity of theparticular compound, the dosing regimen, the application site, theparticular formulation and the condition being treated. As such, it isgenerally not practical to identify specific administration amountsherein; however, those skilled in the art will be able to determineappropriate therapeutically effective amounts based on the guidanceprovided herein, information available in the art pertaining to IRMcompounds, and routine testing. The term “a therapeutically effectiveamount” means an amount of the IRM compound sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,inhibition of TH2 immune response, antiviral or antitumor activity,reduction or elimination of postsurgical scarring, reduction orresolution of actinic keratosis or pre-actinic keratosis lesions,reduction in the recurrence of actinic keratosis, treatment of basalcell carcinoma, genital warts, peri-anal warts, molloscum contagiosum,or protection against uv-induced epidermal neoplasia.

In general, the amount of IRM compound present in a topical formulationof the invention will be an amount effective to treat a targetedcondition, to prevent recurrence of the condition, or to promoteimmunity against the condition. In certain embodiments, the amount orconcentration of IRM compound is at least 3% by weight, such as, forexample, at least 5%, and at least 10%, by weight based on the totalweight of the formulation. In other embodiments, the amount of IRMcompound is at most 10% by weight, such as, for example, at most 5%, atmost 3%, by weight based on the total weight of the formulation. Incertain embodiments, the amount or concentration of IRM compound is atleast 0.02% by weight, such as, for example, at least 0.03%, at least0.10%, and at least 0.30% by weight based on the total weight of theformulation.

Fatty Acids

The topical formulations of the invention include fatty acids. Inparticular, the topical formulations of the invention contain an oleicacid component. As used herein, the term “fatty acid” means a carboxylicacid, either saturated or unsaturated having 6 to 28 carbon atoms, suchas, for example, from 10 to 22 carbon atoms.

The fatty acids, including the oleic acid component, may be present inthe formulation in an amount sufficient to solubilize the IRM compound.In certain embodiments, the amount of oleic acid component is at least0.05% by weight, at least 1.0% by weight, at least 3.0% by weight, atleast 5.0%, at least 10%, at least 15%, or at least 25%, based on thetotal weight of the formulation. In certain embodiments, the amount ofoleic acid component is at most 40% by weight, at most 30% by weight, atmost 15% by weight, or at most 10%, based on the total weight of theformulation.

Compendial grade oleic acid typically contains from 65 to 88 percent(Z)-octadec-9-enoic acid (oleic acid) together with varying amounts ofsaturated and other unsaturated fatty acids. The composition of fattyacids is determined by gas chromatography using the method described inEuropean Pharmacopeia monograph 01/2005:0799.

For certain embodiments, the oleic acid component contains at least 50%,at least 60%, at least 70% or at least 80% oleic acid. For certainembodiments, the oleic acid component contains at least 80% oleic acid.

For certain embodiments, the oleic acid component is substantially freeof polar impurities, such as peroxides. For certain embodiments, theoleic acid component contains less than 10%, less than 5%, less than 1%,or less than 0.1% by weight of polar impurities. For certainembodiments, the oleic acid component has a peroxide value less than 10.For certain embodiments, the oleic acid component has a peroxide valueless than 5.

For certain embodiments, the oleic acid component comprises SUPERREFINED Oleic Acid NF, available from Croda Inc., Edison, N.J., USA.

For certain embodiments, the topical formulations of the invention caninclude fatty acids in addition to those included in the oleic acidcomponent. For example, certain embodiments can include isostearic acid.In some embodiments, the total amount of fatty acids, including those inthe oleic acid component, is at least 0.05% by weight, at least 1.0% byweight, at least 3.0% by weight, at least 5.0%, at least 10%, at least15%, or at least 25%, based on the total weight of the formulation. Incertain embodiments, the total amount of fatty acids, including those inthe oleic acid component, is at most 40% by weight, at most 30% byweight, at most 15% by weight, or at most 10%, based on the total weightof the formulation.

Antioxidants

For certain embodiments, the topical formulations of the invention caninclude an antioxidant.

Suitable antioxidants are those that are pharmaceutically acceptable anddescribed in the International Cosmetic Ingredient Dictionary andHandbook, Ninth Edition, Volume 4, 2002, and in the USP NF 2004: TheUnited States Pharmacopeia, 27^(th) Revision and The National Formulary,22^(nd) Edition.

Examples of suitable antioxidants include ascorbic acid (D and/or Lenantiomers), ascorbyl palmitate (D and/or L enantiomers), butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine (D and/orL enantiomers), propyl gallate, sodium formaldehyde sulfoxylate, sodiumthiosulfate, and tocopherol.

For certain embodiments, the antioxidant is selected from the groupcomprising aromatic hydroxy groups capable of hydrogen atom donation.Examples of such antioxidants include BHA, BHT, propyl gallate, andtocopherol.

For certain embodiments, the antioxidant is selected from the groupconsisting of BHA, BHT, and combinations thereof. For certainembodiments, the antioxidant is BHA.

Preservative System

The formulation often will include a preservative system. Thepreservative system includes one or more compounds that inhibitmicrobial growth (e.g., fungal and bacterial growth) within theformulation (for example, during manufacturing and use). Thepreservative system will generally include at least one preservativecompound, such as, for example, methylparaben, ethylparaben,propylparaben, butylparaben, benzyl alcohol, phenoxyethanol, and sorbicacid or derivatives of sorbic acid such as esters and salts. Variouscombinations of these compounds can be included in the preservativesystem. In some embodiments of the invention, the preservative systemincludes methylparaben, propylparaben and benzyl alcohol.

In some embodiments of the invention, the preservative compound ispresent in an amount of at least 0.01% by weight, such as for example,at least 0.02%, at least 0.03%, at least 0.04%, and at least 0.05%, byweight based on the total weight of the formulation. In otherembodiments of the invention the preservative compound is present in anamount of at most 3%, such as for example, at most 2.5%, at most 2.0%,at most 1.0%, at most 0.5%, at most 0.4%, at most 0.3%, and at most0.2%, by weight based on the total weight of the formulation.

Emollients

The topical formulations of the invention may also include at least oneemollient. Examples of useful emollients include but are not limited tolong chain alcohols, for example, cetyl alcohol, stearyl alcohol,cetearyl alcohol; fatty acid esters, for example, isopropyl mysristate,isopropyl palmitate, diisopropyl dimer dilinoleate; medium-chain (e.g.,8 to 14 carbon atoms) triglycerides, for example, caprylic/caprictriglyceride; cetyl esters; hydrocarbons of 8 or more carbon atoms, forexample, light mineral oil, white petrolatum; and waxes, for example,beeswax. Various combinations of such emollients can be used if desired.

In certain embodiments, the amount of the emollient is at least 1.0% byweight, at least 3.0% by weight, at least 5.0% by weight, or at least10% by weight, based on the total weight of the formulation. In certainembodiments, the amount of emollient is at most 30% by weight, at most15% by weight, or at most 10% by weight, based on the total weight ofthe formulation.

Formulations intended for dermal or topical use typically have amountsof an oil phase and an emollient sufficient to provide desirablequalities such as spreadability and feel.

Viscosity Enhancing Agent

The formulations of the present invention can also comprise aviscosity-enhancing agent. Examples of suitable viscosity enhancingagents include long chain alcohols, for example, cetyl alcohol, stearylalcohol, cetearyl alcohol; cellulose ethers such ashydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, and carboxymethylcellulose; polysaccharide gumssuch as xanthan gum; and homopolymers and copolymers of acrylic acidcrosslinked with allyl sucrose or allyl pentaerythriol such as thosepolymers designated as carbomers in the United States Pharmacopoeia.Suitable carbomers include, for example, those available as CARBOPOL934P, CARBOPOL 971P, CARBOPOL 940, CARBOPOL 974P, CARBOPOL 980, andPEMULEN TR-1 (USP/NF Monograph; Carbomer 1342), all available fromNoveon, Cleveland, Ohio.

In certain embodiments, the amount of the viscosity enhancing agent,when used, is at least 0.1% by weight, at least 0.2% by weight, at least0.5% by weight, at least 0.6% by weight, at least 0.7% by weight, atleast 0.9% by weight, or at least 1.0% by weight, based on the totalweight of the formulation. In certain embodiments, the amount of theviscosity-enhancing agent, when used, is at most 10% by weight, at most5.0% by weight, at most 3.0% by weight, at most 2.0% by weight, or atmost 1.5% by weight, based on the total weight of the formulation.

Emulsifier

The formulations of the invention can additionally comprise anemulsifier. Suitable emulsifiers include non-ionic surfactants such as,for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4oleate, polyoxyethylene(4) lauryl ether, etc. In certain embodiments,the emulsifier is chosen from poloxamers (e.g., PLURONIC F68, also knownas POLOXAMER 188, a poly(ethylene glycol)-block-poly(propyleneglycol)-block-poly(ethylene glycol), available from BASF, Ludwigshafen,Germany) and sorbitan trioleate (e.g., SPAN 85 available from Uniqema,New Castle, Del.).

If included, the emulsifier is generally present in an amount of 0.1% to10% by weight of total formulation weight, for example, from 0.5% to5.0% by weight, and from 0.75% to 4.0% by weight. In certainembodiments, the amount of the emulsifier, if used, is present in anamount of at least 0.1% by weight, at least 0.5% by weight, at least0.75% by weight, at least 1.0% by weight, at least 2.5% by weight, atleast 3.5% by weight, at least 4.0% by weight, or at least 5.0% byweight, based on the total weight of the formulation. In certainembodiments, the amount of the emulsifier, if used, is present in anamount of at most 10% by weight, at most 5.0% by weight, or at most 3.5%by weight, based on the total weight of the formulation.

Some formulations of the invention are oil-in-water emulsions. The waterused in these formulations is typically purified water

Optionally, a formulation of the invention can contain additionalpharmaceutically acceptable excipients such as humectants, such as forexample, glycerin; chelating agents, such as for example,ethylenediaminetetraacetic acid; and pH adjusting agents, such as forexample, potassium hydroxide or sodium hydroxide.

In some instances, a single ingredient can perform more than onefunction in a formulation. For example, cetyl alcohol can serve as bothan emollient and a viscosity enhancer.

Illustrative Formulation

In one embodiment of the present invention, a pharmaceutical formulationincludes:

5% by weight of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine;

28% by weight SUPER REFINED oleic acid;

2.2% by weight cetyl alcohol;

3.1% by weight stearyl alcohol;

3% by weight petrolatum;

3.4% by weight polysorbate 60;

0.6% by weight sorbitan monostearate;

2% by weight glycerin;

0.2% by weight methyl hydroxybenzoate;

0.02% by weight propyl hydroxybenzoate;

0.5% by weight xanthan gum;

2% by weight of benzyl alcohol; and

49.98% by weight water;

wherein the weight percentages are based on the total weight of theformulation.

Methods of Application

Formulations according to the present invention can be applied to anysuitable location, for example topically to dermal and/or mucosalsurfaces. In the case of dermal application, for example, depending onthe IRM compound concentration, formulation composition, and dermalsurface, the therapeutic effect of the IRM compound may extend only tothe superficial layers of the dermal surface or to tissues below thedermal surface. Thus, another aspect of the present invention isdirected to a method for the treatment of a dermal and/or mucosalassociated condition comprising applying to skin one of the foregoingformulations. As used herein, a “dermal and/or mucosal associatedcondition” means an inflammatory, infectious, neoplastic or othercondition that involves a dermal and/or mucosal surface or that is insufficient proximity to a dermal and/or mucosal surface to be affectedby a therapeutic agent topically applied to the surface. Examples of adermal and/or mucosal associated condition include warts, atopicdermatitis, postsurgical scars, lesions caused by a herpes virus, andepidermal neoplasias, such as for example actinic keratosis, pre-actinickeratosis lesions, malignant melanomas, basal cell carcinoma, andsquamous cell carcinoma.

In one embodiment, the formulations can be applied to the surface ofskin for treatment of actinic keratosis (AK). Actinic keratosis arepremalignant lesions considered biologically to be either carcinomain-situ or squamous intraepidermal neoplasia. AK is the most frequentepidermal tumor and is induced by ultraviolet (UV) radiation, typicallyfrom sunlight. Because of its precancerous nature, AK may be consideredthe most important manifestation of sun-induced skin damage.

In some embodiments, the above-described formulations are particularlyadvantageous for dermal and/or mucosal application for a period of timesufficient to obtain a desired therapeutic effect without undesiredsystemic absorption of the IRM compound.

EXAMPLES

The following Examples are provided to further describe variousformulations and methods according to the invention. The examples,however, are not intended to limit the formulations and methods withinthe spirit and scope of the invention.

Test Method

A reversed phase high performance liquid chromatography (HPLC) methodwas used to determine the amount of impurities in cream formulationscontaining oleic acid.

HPLC parameters: Analytical column: ZORBAX RX C8, 5 micron particle,15.0×0.46 cm, (available from Agilent Technologies, Wilmington, Del.,USA); Detector: UV at 308 nm; Mobile phase: gradient mixture of aqueousammonium phosphate buffer (prepared by combining 5.1 mL ofortho-phosphoric acid with 985 mL of water and then adjusting to pH 2.5with concentrated ammonium hydroxide) and acetonitrile; Gradient: startrun at 10% acetonitrile, zero initial hold time, then linear gradient to70% acetonitrile over 15 minutes, zero final hold time; Flow rate: 2.0mL/minute; Injection volume: 200 μL; Run time: 15 minutes.

Sample solution: A portion (about 300 mg) of the cream formulation wasaccurately weighed into a volumetric flask (100 mL). Diluent (50 to 60mL, prepared by combining 250 parts of acetonitrile, 740 parts of waterand 10 parts of hydrochloric acid, all parts by volume) was added to theflask. The flask was vortexed until the cream was completely dispersedand then sonicated for a minimum of 5 minutes. The solution was allowedto cool to ambient temperature and then diluted to volume with diluentand mixed. A portion of the solution was filtered using a syringeequipped with a 0.45 micron polypropylene or polytetralfluoroethylenefilter to provide the sample solution.

Preparation of Cream Formulations

The cream formulations in Table 1 below were prepared using thefollowing method.

Water phase preparation: A paraben premix was prepared by combiningmethyl hydroxybenzoate (methylparaben), propyl hydroxybenzoate(propylparaben), and water; heating the mixture with stiffing until theparabens were dissolved; and then allowing the resulting solution tocool to ambient temperature. Glycerin was added to the premix and themixture was heated to 55±5° C. Xanthan gum was slowly added with mixing.Mixing with heating was continued until the xanthan gum was dispersed.

Oil phase preparation: An imiquimod/oleic acid premix was prepared bycombining imiquimod and the oleic acid and then stiffing at ambienttemperature overnight. Petrolatum, cetyl alcohol, stearyl alcohol,polysorbate 60, sorbitan monostearate, and butylated hydroxyanisole(BHA), if included, were added to the premix. The oil phase was thenheated with stirring to 55±5° C. Benzyl alcohol was added to the oilphase just prior to phase combination.

Phase combination: Both phases were removed from their heat source. Theaqueous phase was added to the oil phase and the emulsion washomogenized at high speed for at least 5 minutes. The cream was placedin an ice/water bath while homogenizing and homogenization was continueduntil the temperature of the cream was 35° C. The homogenizer speed wasreduced and homogenization was continued until the temperature of thecream was 25° C.

Table 1 summarizes creams in A-D in percentage weight-by-weight basis.The formulations were packaged in glass containers.

TABLE 1 Ingredient A B C D ¹Imiquimod 5 5 5 5 ²Oleic acid, NF 28 28 — —³SUPER REFINED oleic acid, NF — — 28 28 Cetyl alcohol 2.2 2.2 2.2 2.2Stearyl alcohol 3.1 3.1 3.1 3.1 Petrolatum 3 3 3 3 Polysorbate 60 3.43.4 3.4 3.4 Sorbitan monostearate 0.6 0.6 0.6 0.6 Benzyl alcohol 2 2 2 2BHA — 1 — 1 Glycerin 2 2 2 2 Methylparaben 0.2 0.2 0.2 0.2 Propylparaben0.02 0.02 0.02 0.02 Xanthan gum 0.5 0.5 0.5 0.5 Water qs 100 qs 100 qs100 qs 100 ¹1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine ²J. T.Baker, a division of Mallinckrodt Baker, Inc, Phillipsburg, NJ, USA³Croda, Inc, Edison, NJ, USA

One set of containers was stored at ambient conditions; the samples usedto determine initial values came from these containers. The remainingcontainers were stored in a constant temperature and humidity chamber at40° C. at 75% relative humidity. At selected time points, containerswere removed from the chamber and then stored at ambient conditionsuntil analyzed. Samples were analyzed using the test method describedabove for impurities. At the 2, 4, and 6 month time points samples weretaken from both the top and the bottom of the containers. The resultsare shown in Table 2 below where each value is the result of a singledetermination. Values are not normalized for weight loss that may haveoccurred during storage.

TABLE 2 Impurities (% wt/wt) Timepoint A B C D ¹Initial - top 0.09 0.080.02 0.03 ²2 months - top 0.25 0.32 0.07 0.09 ²2 months - bottom 0.330.30 0.04 0.15 ³4 months - top 0.42 0.76 0.18 0.15 ³4 months - bottom0.46 0.56 0.04 0.29 ⁴6 months - top 0.81 0.30 0.07 0.14 ⁴6 months -bottom 0.49 0.29 0.04 0.07 ¹Creams A, B, C, and D were analyzed 16 days,15 days, 14 days, and 15 days respectively after they were prepared.²All samples were analyzed 10 days after the containers were removedfrom the constant temperature and humidity chamber. ³All samples wereanalyzed 12 days after the containers were removed from the constanttemperature and humidity chamber. ⁴All samples were analyzed 7 daysafter the containers were removed from the constant temperature andhumidity chamber.

The complete disclosures of the patents, patent documents andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. In case of conflict,the present specification, including definitions, shall control. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. Illustrative embodiments and examples are provided asexamples only and are not intended to limit the scope of the presentinvention. The scope of the invention is limited only by the claims setforth as follows.

1. A method of controlling formation of 1-(2-methylpropyl)-1Himidazo[4,5-c]quinolin-4-amine (imiquimod) related impurities in apharmaceutical cream formulated with imiquimod and an oleic acidcomponent during storage of the pharmaceutical cream prior toapplication of the pharmaceutical cream to a dermal or mucosal surface,said method comprising: formulating the pharmaceutical cream withimiquimod and a pharmaceutically acceptable vehicle including an oleicacid component, wherein the oleic acid component contains at least about80% oleic acid by weight as a fatty acid and has a peroxide value of nomore than about 5 milliequivalents of oxygen per kilogram and containsless than about 1% by weight polar impurities at or prior to formulationof the pharmaceutical cream; storing the formulated pharmaceuticalcream; and forming a reduced amount of imiquimod-related impurities inthe pharmaceutical cream during said storing of the pharmaceuticalcream, as compared to an amount of imiquimod-related impurities formedin an identical pharmaceutical imiquimod cream but further formulatedwith butylated hydroxyanisole (BHA) when the pharmaceutical cream andthe identical pharmaceutical imiquimod cream are each stored underidentical storage conditions for an equal period of time afterformulation for up to about six months.
 2. The method of claim 1,wherein said pharmaceutical cream has been stored for up to about sixmonths prior to the use of the pharmaceutical cream.
 3. The method ofclaim 1, wherein said pharmaceutical cream has been stored for up toabout four months prior to the use of the pharmaceutical cream.
 4. Themethod of claim 1, wherein said pharmaceutical cream has been stored forup to about two months prior to the use of the pharmaceutical cream. 5.The method of claim 1, wherein said pharmaceutical cream furthercomprises an antioxidant selected from the group consisting of butylatedhydroxyl toluene (BHT) and butylated hydroxyanisole (BHA).
 6. The methodof claim 1, wherein the imiquimod is present in an amount of not morethan 10% by weight based on the total weight of said pharmaceuticalcream and wherein the oleic acid component is present in an amount of nomore than about 40% by weight based on the total weight of saidpharmaceutical cream.
 7. The method of claim 1, wherein the imiquimod ispresent in an amount of about 5% by weight based on the total weight ofsaid pharmaceutical cream and wherein the oleic acid component ispresent in an amount of about 28% by weight based on the total weight ofsaid pharmaceutical cream.
 8. The method of claim 1, wherein theimiquimod is present in an amount of about 5% by weight based on thetotal weight of said pharmaceutical cream and wherein the oleic acidcomponent is present in an amount of about 25% by weight based on thetotal weight of said pharmaceutical cream.
 9. The method of claim 1,wherein said oleic acid component is Super Refined oleic acid NF.